Development of Bifunctional Chiral Thioureas and Thiosquaramides in the Synthesis of Betti Bases

Bifunctional thioureas and, for the first time, bifunctional thiosquaramides as organocatalysts were used in the asymmetric Betti reaction involving 1-, 2-naphthols and hydroxyquinoline with N-tosylimine and ketimine. The described methodology affords direct access to chiral aminoarylnaphthols in excellent yield (up to 98%) with high enantioselectivity (up to 80% ee) and enantioenriched 3-amino-2-oxindoles (up to 78% yield, up to 98% ee).


Introduction
The Betti reaction, alternatively referred to as the Aza-Friedel-Crafts reaction, represents an important variant of the Mannich reaction and is one of the most important C-C bond-forming reactions in organic chemistry.The Betti reaction is a simple multicomponent condensation between 2-naphthol, aryl aldehydes, and amines that leads to aminobenzylnaphthols, the so-called Betti bases [1][2][3].Over the past decade, many research groups have reported different variants of this reaction, generally using a pre-formed imine that is often protected as a sulfonamide [4][5][6].Aminoarylnaphthols are a class of molecules found in natural and synthetic compounds with a wide range of interesting activities and applications.Chiral Betti bases have been widely used in optoelectronics, but their biological properties, such as anticancer, anti-bacterial, antioxidant, anti-inflammatory, antipain, antihypertensive, anti-Alzheimer, and bradycardia activities, deserve special attention [7].In addition, chiral Betti bases have been proven to be useful ligands and auxiliaries in asymmetric synthesis [7][8][9][10].Their widespread applications have generated considerable interest in developing asymmetric methods for their preparation.In 2010, the Hui group reported an enantioselective Betti reaction of 2-naphthol with tosylimines catalyzed by a dinuclear zinc complex, to prepare chiral Betti base derivatives with high yields and excellent enantioselectivity of up to 96% [11].Subsequent studies were carried out using quinine-squaramide organocatalysts [12].The results obtained by Chimni and Wang's group demonstrated that αand β-naphthol derivatives react readily with various aromatic and heteroaromatic N-sulfonylimines in the presence of Cinchona alkaloid derived bifunctional organocatalyst [13,14].The reaction of naphthols with isatinderived ketimines turned out to be more demanding.In 2015, Pedro and Khan's groups, respectively, reported an enantioselective version of this reaction organocatalyzed by the same quinine-derived thiourea to yield chiral 3-amino-2-oxindoles in high yields with excellent enantioselectivity [15][16][17].Two years later, Tanyeli used bulky cinchona-derived squaramides in the same transformation on naphthols [18].In 2020, Pedrosa and coworkers reported that aminoethyl polystyrene-supported cinchona-thiourea derivatives could be recovered and reused in a highly enantioselective aza-Friedel-Crafts reaction of different naphthols with a variety of N-Boc ketimines derived from isatin [19].Recently, Wang and Jin reported simple Takemoto-type thiourea-catalyzed reactions of β-naphthols with isatines leading to 3-(naphthalen-1-yl)-3-amino-2-oxindoles with excellent 89-95% yield and high enantioselectivity (90-97% ee) [20].We would also like to mention the enantioand diastereoselective cascade Betti/aza-Michael reaction of phenols and N-tosylimin containing Michael acceptor catalyzed by bifunctional thiourea organocatalysts leading to 1,3-disubstituted isoindolines [21].To our knowledge, these are the most important, if not the only, literature reports on the asymmetric Betti reaction.Due to the high demand for the development of this reaction, we decided to test thiourea and, for the first time, thiosquaramide catalysts, compare the obtained results with those already published, and then draw general conclusions regarding the use of organocatalysts of this type in the reactions of αand β-naphthols and 6-hydroxyquinoline with tosylimine and ketimine.Catalysts of this type have a number of advantages: their synthesis is uncomplicated, and the reactions involving them proceed under mild conditions, without metal cation.Moreover, the presence of a thiourea/thiosquaramide bridge and strongly acidic protons leads to the formation of strong hydrogen bonds and activation of the substrate.While bifunctional chiral thioureas have been widely used in asymmetric synthesis [22][23][24], including the Betti reaction, bifunctional chiral thiosquaramides were used only in Michael addition [25][26][27][28][29], asymmetric Michael-Henry tandem reaction [30], and the addition of lawsone to β,γ-unsaturated α-keto ester [31].

Results and Discussion
Bifunctional thioureas were prepared in one step, as previously described [32][33][34].The reaction of appropriate, commercially available isothiocyanates with amines leads to thioureas in near quantitative yields.Two of the synthesized thioureas, 2 and 5, are new compounds, while the bifunctional Takemoto catalyst 3 is commercially available (Figure 1).Thiosquaramides 8-11 were prepared in four steps from 3,4-dihydroxycyclobut-3-en-1,2dione (squaric acid).In the first step, esterification of the square acid with cyclopentanol gave dicyclopentyl squarate [25,31].Subsequently, dithionation with Lawesson's reagent led to dicyclopentyl dithiosquarate, which was found to be an excellent platform for the synthesis of 8-11 (Figure 1).Disubstituted thiosquaramide derivatives reacted vigorously with primary amines-first with 3,4-bis(trifluoromethyl)aniline and then with the appropriate amine having a chiral center and a tertiary amine.The last step was carried out using the traditional solvent method, but also using mechanochemistry.It should be emphasized that the use of a ball mill resulted in a significant increase in chemical efficiency.Due to the possibility of creating rotamers and zwitterionic species by bifunctional thiosquaramides, especially those possessing an aryl substituent, we transformed them into appropriate hydrochlorides, which resulted in simplifying their spectra and sharpening many signals [31].
To study the feasibility and enantioselectivity of the Betti reaction, a bifunctional catalyst 1 which consists of H-bond donor and amine moieties was screened for a model reaction of 1-naphthol (12) with N-tosylimine (13) in toluene at room temperature (Scheme 1 and Table 1).The desired product 14 was isolated in good yield (98%) and with 75% ee after 20 h (Table 1, entry 2) when a threefold excess of 1-naphthol relative to imine was used.
To further improve the enantioselectivity of the transformation, we investigated a variety of different reaction conditions, including the solvent, temperature, and catalyst loading (Table 2).
The obtained results revealed that the solvent effect had a significant impact on the efficiency of the reaction.Toluene was found to be optimal (Table 1, entry 2), while reactions carried out in THF, ACN, o-xylene, and DCM resulted in a decrease in yield and enantioselectivity (Table 1, entries 9-12).The screening of catalyst loading exhibited that 10 mol% equivalent of 1 was optimal, while 5 mol% and 30 mol% offered no improvement in the asymmetric induction (Table 1, entries 7-8).It is noteworthy that the temperature also influenced the reaction-after lowering it from rt to 0 • C, a slight increase in enantioselectivity was observed (Table 1, entry 6).Based on these experiments, the optimized conditions were determined to be toluene as the solvent with a 10 mol% loading of catalyst 1, entry 6).The absolute configuration of the product was assigned as (S) based on a comparison of the optical rotation of the product material with a value from the literature [14,32].To study the feasibility and enantioselectivity of the Betti reaction, a bifunctional catalyst 1 which consists of H-bond donor and amine moieties was screened for a model reaction of 1-naphthol (12) with N-tosylimine (13) in toluene at room temperature (Scheme 1 and Table 1).The desired product 14 was isolated in good yield (98%) and with 75% ee after 20 h (Table 1, entry 2) when a threefold excess of 1-naphthol relative to imine was used.
To further improve the enantioselectivity of the transformation, we investigated a variety of different reaction conditions, including the solvent, temperature, and catalyst loading (Table 2).Scheme 1. Betti reaction of 1-naphthol (12) with N-tosylimine 13.Reagents and conditions: 1-naphthol (0.15 mmol, 3 eq.),N-tosylimine (0.05 mmol, 1 eq.), solvent (1 mL), molecular sieves 4 Å, 20 h. 1 Isolated product. 2 Determined by HPLC analysis, Chiralpak AD-  To study the feasibility and enantioselectivity of the Betti reaction, a bifunctional catalyst 1 which consists of H-bond donor and amine moieties was screened for a model reaction of 1-naphthol (12) with N-tosylimine (13) in toluene at room temperature (Scheme 1 and Table 1).The desired product 14 was isolated in good yield (98%) and with 75% ee after 20 h (Table 1, entry 2) when a threefold excess of 1-naphthol relative to imine was used.
With the optimized conditions in hand, we evaluated the general applicability of this asymmetric Betti reaction using bifunctional thioureas 1-7 (Table 2 entries 1-7).All tested organocatalysts gave the expected product in high yields (80-98%) with moderate to high enantioselectivities (58-80% ee).(R,R)-piperidine-based thiourea 1 and Takemoto catalyst 3 with the 3,5-bis(trifluoromethyl)phenyl moiety provided the best yield and enantioselectivity (Table 2, entries 1 and 3).The obtained results prove the higher efficiency of thiourea catalysts having at one of the nitrogen atoms an aryl group with strongly electron-acceptor substituents (CF 3 ), which by increasing the acidity of the N-H bond facilitates the formation of a hydrogen bond with the substrate.In contrast, bifunctional organocatalysts 6-7 without the aminocyclohexyl moiety showed lower asymmetric induction (Table 2, entries 6-7).
To rationalize the stereochemical outcome, a dual activation for the thiourea and thiosquaramide-catalyzed asymmetric Betti reaction of 1-naphthol (12) with N-tosylimine 13 is proposed in Scheme 2. Based on previous literature reports [13, [22][23][24] and the observed stereochemistry, a transition state involving a ternary complex between the catalyst and the substrates can be proposed.Both thiourea and thiosquaramide catalysts promote the reaction in a dual manner: activating N-tosylimine through forming H-bond with the thiourea/thiosquaramide motif and enhancing the nucleophilicity of 1-naphthol by the tertiary amine moiety of catalyst.As shown in Scheme 2, a configuration of the product was determined by the absolute configuration of the carbon atom at the thioamide nitrogen atom of the thiourea/thiosquaramide moiety.For organocatalysts 1-5 and 8-9, the activated 1-naphthol is capable of nucleophilic attack from C2 on the Re face of the imine providing the S enantiomer of the product.On the other hand, for organocatalysts 6-7 and 10-11 with the opposite absolute configuration (the compatibility of the relative configuration results from the different priority of the substituents), the attack of the nucleophile on the Si face of the imine is favored which leads to (R)-16.
promote the reaction in a dual manner: activating N-tosylimine through forming H-bond with the thiourea/thiosquaramide motif and enhancing the nucleophilicity of 1-naphthol by the tertiary amine moiety of catalyst.As shown in Scheme 2, a configuration of the product was determined by the absolute configuration of the carbon atom at the thioamide nitrogen atom of the thiourea/thiosquaramide moiety.For organocatalysts 1-5 and 8-9, the activated 1-naphthol is capable of nucleophilic attack from C2 on the Re face of the imine providing the S enantiomer of the product.On the other hand, for organocatalysts 6-7 and 10-11 with the opposite absolute configuration (the compatibility of the relative configuration results from the different priority of the substituents), the attack of the nucleophile on the Si face of the imine is favored which leads to (R)-16.

Scheme 2. Proposed dual activation for the thiourea and thiosquaramide-catalyzed asymmetric Betti reaction of 1-naphthol with N-tosylimine.
To demonstrate the generality of the 1-11-promoted asymmetric Betti reaction, other imines and naphthols were explored (Tables 3-7).The optimization of the reaction conditions of 2-naphthol (15) with N-tosylimine 13 (Scheme 3) catalyzed by thiourea 1 indicated that the use of substrates in the molar ratio naphthol:imine = 3:1, 10 mol% of 1 in toluene at 0 °C was optimal for this transformation and led to chiral product 16 in 98% yield and 54% ee value (Table 3, entry 2).Scheme 2. Proposed dual activation for the thiourea and thiosquaramide-catalyzed asymmetric Betti reaction of 1-naphthol with N-tosylimine.
In the next step, we decided to react 2-naphthol (15) with imine 13 in the presence of other organocatalysts 2-11 (Table 4).
All tested bifunctional thioureas 1-7 gave product 16 in high yields (65-98%) but with low enantiomeric excesses (6-61% ee, Table 4, entries 1-7).The obtained results showed that Takemoto-type organocatalysts 1-5 were less effective in this transformation.In contrast, all bifunctional thiosquaramides 8-11 and their hydrochlorides slightly improved the asymmetric induction (Table 4, entries 8-15).Although the yields of reactions catalyzed by thiosquaramides were low compared to thioureas, the ee values were higher (46-71% ee).Nevertheless, this is the first example of the use of thiosquaramide organocatalysts in the reaction of 2-naphthol with imine 13.Their higher catalytic activity in the reaction of 2-naphthol compared to 1-naphthol should also be noted (Table 2 vs. Table 4).
In the next stage of our research, we decided to test the catalytic activity of thiourea 1 in the reaction of 6-hydroxyquinoline as a nucleophile (17) with N-tosylimine 13.Unfortunately, despite many attempts, we were unable to obtain the desired product.
Taking into account the obtained results, we have proposed the possible transition state shown in Scheme 5. Bifunctional organocatalysts are responsible for the preorientation and simultaneous activation of electrophile via H-bond donor thiourea/thiosquaramide moiety and the enhancement of the nucleophilicity of 6-hydroxyquinoline by the tertiary amine unit of catalyst [16][17][18].Generally, nucleophile attacks from C-5 of 6-hydroxyquinoline on the Si face of ketimine results in the S configuration of product in the case of Takemoto-type organocatalysts 1-5 and 9, while in reactions catalyzed by 6-7 and 10-11 Si face of ketimine becomes less available and the formation of the R isomer is favored.Finally, the reactions of naphthols 12 and 15 with ketimine 18 were developed (Scheme 6, Table 7).For testing, we chose thiourea 7, which reacted best with 6hydroxyquinoline, and its thiosquaramide counterpart 11.The obtained results, similarly to those obtained for the reaction 6-hydroxyquinoline (17) with ketimine 18, indicated a higher activity of thiourea 7 compared to thiosquaramide 11. 3-Substituted 3-amino-2oxindoles were obtained in moderate yield (53%) and enantioselectivity (78% ee) in the Scheme 5. Proposed dual activation for the thiourea and thiosquaramide-catalyzed asymmetric Betti reaction of 6-hydroxyquinoline with ketimine.

Materials and Methods
Commercially available chemicals used in this work were purchased from Merck (Darmstadt, Germany) and were used as supplied, without additional purification.NMR spectra were recorded in CDCl 3 on a Bruker Avance III (600 MHz for 1 H NMR, 150 MHz for 13 C NMR); coupling constants are reported in hertz (Hz).The chemical shift values were expressed in ppm (part per million) with tetramethylsilane (TMS) as an internal reference.The rotations were measured using an Anton Paar MCP 500 polarimeter.Melting points measured on the DigiMelt apparatus are uncorrected.The milling treatments were carried out in a vibrating Retsch Mixer Mill 400 (vbm).Milling load is defined as the sum of the mass of the reactants per free volume in the jar.All the reactions using a vibratory ball mill were performed at 25 Hz under air with no interruption of the milling.Chromatographic purification of compounds was achieved with 230-400 mesh size silica gel.The progress of reactions was monitored by silica gel thin-layer chromatography plates (Merck TLC Silicagel 60 F254).The enantiomeric excess was determined by HPLC (1260 Infinity, Agilent Technologies, Santa Clara, CA, USA), employing a Chiralpak AD-H or OD-H column (25 cm × 4.6 mm).

Conclusions
In conclusion, we have developed an enantioselective Betti reaction of 1-and 2naphthols and 6-hydroxyquinoline with tosylimine and ketimine compounds using thioureas and, for the first time, thiosquaramide bifunctional organocatalysts.
We obtained synthetically and medicinally useful chiral aminoarylnaphthols, in excellent yield (up to 98%) with high enantioselectivity (up to 80% ee) and enantioenriched 3-amino-2-oxindoles (up to 78% yield, up to 98% ee).Moreover, we have shown that Takemoto-type thioureas most efficiently catalyze the reaction of 1-naphthol with N-tosyl imine (80% ee), while in the reaction of 2-naphthol with N-tosyl imine, the bifunctional thiosquaramides organocatalysts demonstrated higher catalytic activity (up to 71% for thiosquaramide 8 vs. 61% ee for thiourea 6).The reaction of 6-hydroxyquinoline with isatinderived N-Boc ketimine led regioselectively to the alkylated at C-5 chiral product with moderate yield and enantioselectivity, and thiourea 7, which lacked the cyclohexylamine moiety and performed best under these conditions (up to 98% ee) while its thiosquaramide counterpart generated up to 10% ee.Similar observations were made for the reactions of 1and 2-naphthols with 6-hydroxyquinoline.